2,5-Inter-o-phenylene-3,4-dinor-5,9α-epoxy-6-iodo-PGF1 compounds

ABSTRACT

The present invention provides 2,5-inter-o-phenylene-3,4-dinor-6,9α-epoxy-6β-6-iodo-PGF 1  compounds. These compounds are intermediates for preparing 2,5-inter-o-phenylene-3,4-dinor-prostacyclin analogs, which are useful for pharmacological purposes, e.g., as antithrombotic agents.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of Ser. No. 062,443, now U.S. Pat. No.4,312,810 filed July 31, 1979, which is a continuation-in-part of Ser.No. 962,845, filed Nov. 22, 1978, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel prostacyclin analogs andintermediates for their production. In particular, the present inventionrelates to prostacyclin intermediates useful in the production of2,5-inter-o-phenylene-3,4-dinor-prostacyclin analogs. Most particularlythe present invention provides2,5-inter-o-phenylene-3,4-dinor-5,9α-epoxy-6-iodo-PGF₁ compounds. Thepreparation and use of the novel compounds described herein isincorporated here by reference U.S. Pat. No. 4,281,113.

SUMMARY OF THE INVENTION

The present invention particularly provides a prostacyclin intermediateof formula IX ##STR1## wherein R₂₈ is --OR₁₀, --CH₂ OR₁₀, hydroxy,hydroxymethyl, or hydrogen, wherein R₁₀ is a blocking group removable bymild acidic hydrolysis;

wherein Y₁ is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --CH₂ CH₂ --, or

(4) --C.tbd.C--,

wherein M₈ is α-R₅ :β-OR₁₀ or α-OR₁₀ :β-R₅, wherein R₅ is hydrogen ormethyl and R₁₀ is as defined above, or

α-R₅ :β-OH or α-OH:β-R₅, wherein R₅ is as defined above;

wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ andα-R₄ -β-R₃, wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being thesame or different, with the proviso that one of R₃ and R₄ is fluoro onlywhen the other is hydrogen or fluoro;

wherein R₇ is

(1) --(CH₂)_(m) --CH₃, wherein m is an integer from one to 5, inclusive;

(2) phenoxy;

(3) phenoxy substituted by one, 2 or 3 chloro, fluoro, trifluoromethyl,alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbonatoms, inclusive, with the proviso that not more than two substituentsare other than alkyl;

(4) phenyl;

(5) phenyl substituted by one, 2 or 3 chloro, fluoro, trifluoromethyl,alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbonatoms, inclusive, with the proviso that not more than two substituentsare other than alkyl;

(6) phenylmethyl, phenylethyl, or phenylpropyl; or

(7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, 2 or3 chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms,inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with theproviso that not more than two substituents are other than alkyl; withthe proviso that R₇ is phenoxy or substituted phenoxy, only when R₃ andR₄ are hydrogen or methyl, being the same or different;

wherein R₁ is

(1) hydrogen;

(2) alkyl of one to 12 carbon atoms, inclusive;

(3) cycloalkyl of 3 to 10 carbon atoms, inclusive;

(4) aralkyl of 7 to 12 carbon atoms, inclusive;

(5) phenyl;

(6) phenyl substituted with one, 2 or 3 chloro or akyl of one to 3carbon atoms; or

(7) phenyl substituted in the para position by

(a) --NH--CO--R₂₅

(b) --CO--R₂₆

(c) --O--CO--R₂₇

(d) --CH═N--NH--CO--NH₂

wherein R₂₅ is methyl, phenyl, acetamidophenyl, benzamidophenyl, or--NH₂ ; R₂₆ is hydrogen, methyl, phenyl, --NH₂, or methoxy; and R₂₇ isphenyl or acetamidophenyl, inclusive, or a pharmacologically acceptablesalt thereof when R₁ is hydrogen.

The novel prostaglandin analogs prepared from the above intermediatesare useful for a variety of prostacyclin-like pharmacological purposes,particularly and especially as inhibitors of platelet aggregation invivo and in vitro. Thus, these prostacyclin analogs are useful for avariety of pharmacological and therapeutical purposes, e.g., asantithrombotic agents.

We claim:
 1. A prostacyclin intermediate of formula IX ##STR2## whereinR₂₈ is --OR₁₀, --CH₂ OR₁₀, hydroxy, hydroxymethyl, or hydrogen, whereinR₁₀ is a blocking group removable by mild acidic hydrolysis;wherein Y₁is (1) trans--CH═CH--, (2) cis--CH═CH--, (3) --CH₂ CH₂ --, or (4)--C.tbd.C--, wherein M₈ is α-R₅ :β-OR₁₀ or α-OR₁₀ :β-R₅, wherein R₅ ishydrogen or methyl and R₁₀ is as defined above, or α-R₅ :β-OH orα-OH:β-R₅, wherein R₅ is as defined above; wherein L₁ is α-R₃ :β-R₄,α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ and α-R₄ :β-R₃, wherein R₃ and R₄are hydrogen, methyl, or fluoro, being the same or different, with theproviso that one of R₃ and R₄ is fluoro only when the other is hydrogenor fluoro; wherein R₇ is (1) --(CH₂)_(m) --CH₃, wherein m is an integerfrom one to 5, inclusive; (2) phenoxy; (3) phenoxy substituted by one, 2or 3 chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms,inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with theproviso that not more than two substituents are other than alkyl; (4)phenyl; (5) phenyl substituted by one, 2 or 3 chloro, fluoro,trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy ofone to 3 carbon atoms, inclusive, with the proviso that not more thantwo substituents are other than alkyl; (6) phenylmethyl, phenylethyl, orphenylpropyl; or (7) phenylmethyl, phenylethyl, or phenylpropylsubstituted by one, 2 or 3 chloro, fluoro, trifluoromethyl, alkyl of oneto 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms,inclusive, with the proviso that not more than two substituents areother than alkyl; with the proviso that R₇ is phenoxy or substitutedphenoxy, only when R₃ and R₄ are hydrogen or methyl, being the same ordifferent; wherein R₁ is (1) hydrogen; (2) alkyl of one to 12 carbonatoms, inclusive; (3) cycloalkyl of 3 to 10 carbon atoms, inclusive; (4)aralkyl of 7 to 12 carbon atoms, inclusive; (5) phenyl; (6) phenylsubstituted with one, 2 or 3 chloro or alkyl of one to 3 carbon atoms;or (7) phenyl substituted in the para position by(a) --NH--CO--R₂₅ (b)--CO--R₂₆ (c) --O--CO--R₂₇ (d) --CH═N--NH--CO--NH₂ wherein R₂₅ ismethyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH₂ ; R₂₆ ishydroxy, methyl, phenyl, --NH₂, or methoxy; and R₂₇ is phenyl oracetamidophenyl, inclusive, or a pharmacologically acceptable saltthereof when R₁ is hydrogen.